1. Field of the Invention
This invention relates to ALK inhibitors of general formula:
in which R1, R2, X1, X2 and X3 have the meanings indicated below, and to processes for the preparation of, compositions containing and the uses of such derivatives.
2. Description of Related Art
Anaplastic lymphoma kinase (ALK) is a member of the receptor tyrosine kinase superfamily, and at an amino acid sequence level is most closely related to members such as Ros-1, leucocyte tyrosine kinase, the insulin receptor and cMet (hepatic growth factor receptor) (Kostich M et al, Genome Biology, 2002, 3, 1-12). As with all members of this gene family, it possesses an extracellular ligand binding domain, a transmembrane spanning sequence, and an intracellular kinase catalytic region/signalling domain. The identity of the signalling ligand for ALK is not yet elucidated and different mechanisms have been proposed in the literature (Stoica G E et al J. Biol. Chem. 2001, 276, 16772-16779; Stoica G E et al J Biol Chem 2002, 277, 35990-35999; Mewng K et al, PNAS 2000, 97, 2603-2608; Perez-Pinera P et al, J Biol Chem 2007, 282, 28683-28690). The stimulation of ALK leads to an intracellular signalling cascade via phopholipase-C γ, PI3Kinase and STAT3 (amongst other signalling proteins) (Turner S D et al, Cell Signal 2007, 19, 740-747).
ALK is largely expressed in the developing nervous system (Iwahara T et al, Oncogene 1997, 14, 439-449). Its relative abundance does tend to decrease in the adult animal, though its expression is maintained in certain regions of the brain, spinal cord and the eye (Vernersson E et al, Gene Expression Patterns, 2006, 6, 448-461).
Investigation of the biological role of ALK in cell culture systems, such as neuronal type cells, has suggested a role in neuronal differentiation (Souttou B, et al, J Biol Chem, 2001, 276, 9526-9531). Its role in-vivo has emerged from study of the ALK knockout mouse (Bilsland J G et al, Neuropsychopharmacology 2008, 33, 685-700). This mouse is viable and has no overt phenotype. This mouse does however have an increased level of neural progenitor cells in the hippocampus (a region of the brain known to be a site of “neurogenesis”) and also showed changes in certain behavioral tests considered to be a measure of antidepressant activity (the tail suspension test and the Porsolt swim test), and in the novel object-recognition test (considered to be a measure of cognitive performance). Neurochemical analysis of the ALK knockout mouse brains also revealed an increase in dopaminergic signalling within the frontal cortex. These results lead the authors to suggest that one role of ALK in the adult brain may be to regulate the function of the frontal cortex and hippocampus, with potential implications for psychiatric and neurological disease.
ALK also has an important role in oncology (Webb T R et al, Expert Reviews in Anticancer Therapy 2009 9 331-355). Point mutations in the full length ALK enzyme that lead to activation of the enzyme, and also increase in expression of the full length enzyme, have both been shown to lead to neuroblastoma. In addition, the fusion of ALK with other proteins due to genetic translocation events, has also been shown to lead to activated kinase domain associated with cancer. A number of such ALK translocations leading to gene fusions are seen in lymphomas, the most prevalent being the nucleophosmin (NPM)-ALK fusion seen in anaplastic large cell lymphomas. ALK fusion with EML4 leads to a chimeric protein (EML4-ALK) thought to be responsible for a small percentage of non small cell lung carcinomas (NSCLC) (Soda M et al, Nature 2007 448 561-567).
Crizotinib is a potent dual tyrosine kinase inhibitor (TKI) targeting c-Met and ALK that has recently found application in the treatment of NSCLC patients harbouring the EML4-ALK fusion event (Kwak et al, New Eng. J. of Med. 2010 363 18 1693-1703). Crizotinib is disclosed in PCT Publication No. WO 2006/021884 and U.S. Pat. No. 7,858,643. While response to treatment with crizotinib in the appropriate subpopulation of NSCLC patients has been promising, a recent case has revealed acquired resistance to crizotinib treatment. Acquired TKI resistance has been seen with other targeted therapies such as in epidermal growth factor receptor (EGFR) mutant lung cancers (Bean J, et al Proc. Nat. Acad. Sci. 2007 104 20932-20937). As a result, there is a need for finding therapeutics active against cells resistant to TKIs, e.g. crizotinib.
In the case of reported acquired resistance of crizotinib, a patient (positive for the EML4-ALK gene fusion) enrolled in a clinical trial of crizotinib on Nov. 28, 2008. The patient responded to the drug for the first 5-months showing partial response over that time but not a complete eradication of their pleural effusion. After 5-months of treatment, the patient's tumor abruptly began growing, and the patient was withdrawn from trial on May 25, 2009. A sample of the patient's pleural effusion was taken and molecular analysis revealed a L1196M and a C1156Y mutation in the EML4-ALK protein (Choi Y L et al, N. Engl. J. Med. 2010 363 18 1734-1739). As crizotinib therapy becomes more widely available to patients harbouring the EML4-ALK gene fusion event, it is likely that the L1196M and C1156Y mutations and possibly other mutations will play a more prevalent role in acquired resistance to crizotinib therapy.
All of these examples clearly mark out ALK as an important target in ALK dependent tumours.
Accordingly, there is a need for ALK inhibitors and EML4-ALK inhibitors that would have an appropriate pharmacological profile, for example in terms of potency, selectivity, pharmacokinetics, ability to cross the blood brain barrier and duration of action. More specifically, there is a need for ALK inhibitors that inhibit the EML4-ALK L1196M mutated protein. In this context, the present invention relates to novel ALK inhibitors.